Despite intensive study, the immune responses associated with protective immunity against HIV infection remain poorly understood. Analysis of cell mediated immune responses induced by live attenuated SIV offers an ideal research setting in which to define specific mechanisms that may play a role in mediating protection. Work completed during the initial funding period has demonstrated that animals vaccinated with SIV239deltanef or SIV239delta3 develop vigorous SIV-specific cytotoxic T lymphocyte response and that CD8+ lymphocytes from animals infected with live-attenuated SIV strains are able to inhibit SIV replication through both MHC-restricted mechanisms and the production of soluble factors. Prospective analysis of SIV-specific CTL responses in animals infected with different live attenuated SIV strains suggest that induction of strong SIV-specific immune responses correlates with protection against vaginal challenge. The overall goal of the current proposal is to extend our understanding of cell-mediated immune responses generated by live attenuated SIV strains, both at systemic and mucosal sites, and to carry out experiments that more definitively address the role of cell mediated immune responses in protective immunity. Specific aims include: 1. To further characterize cell-mediated immune responses induced by infection with attenuated SIV vaccines, including analysis of antigen-specific cytokine responses and characterization of soluble factors able to suppress SIV replication; 2. To correlate CTL responses with protection against challenge with heterologous strains of SIV; 3. To analyze cell-mediated immune responses in mucosal sites and following routes of immunizations and 4. To determine the role of cell-mediated immune responses in mediating protecting immunity using adoptive transfer of T cells in genetically-identical animals. Information from these studies should provide valuable information about the role that cell mediated immune responses play in mediated resistance against challenge with SIV and HIV.